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First Published Online March 13, 2009
The Oncologist, Vol. 14, No. 3, 233-239, March 2009; doi:10.1634/theoncologist.2008-0156
© 2009 AlphaMed Press
Head and Neck Cancers |
Thyroid Storm After Intensity-Modulated Radiation Therapy: A Case Report and Discussion
aDepartment of Radiation Oncology, Vanderbilt University Medical Center, Nashville, Tennessee, USA; bTennessee Oncology, Franklin, Tennessee, USA; c Maury Regional Medical Center, Columbia, Tennessee, USA
Key Words. Thyroid storm • IMRT • Head and neck cancer • Thyrotoxicosis
Correspondence: Anthony J. Cmelak, M.D., Vanderbilt University Medical Center, 1301 Medical Center Drive, B-901 TVC, Nashville, Tennessee 37211, USA. Telephone: 615-322-2555; Fax: 615-343-6589; e-mail: Anthony.Cmelak{at}Vanderbilt.edu
Received July 22, 2008; accepted for publication February 12, 2009; first published online in THE ONCOLOGIST Express on March 13, 2009.
Disclosures: Roberto Diaz: None; Marc D. Blakey: None; Patrick B. Murphy: None; A. Keith Cryar: None; Anthony J. Cmelak: Consultant/advisory role: Amgen, Bristol-Myers Squibb, Sanofi-Aventis; Honoraria: Bristol- Myers Squibb, Sanofi-Aventis.
The content of this article has been reviewed by independent peer reviewers to ensure that it is balanced, objective, and free from commercial bias. No financial relationships relevant to the content of this article have been disclosed by the independent peer reviewers.
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ABSTRACT |
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A 43-year-old man with locally advanced squamous cell carcinoma of the base of tongue was treated with induction chemotherapy followed by intensity-modulated radiation therapy (IMRT). Within 20 days post-treatment, the patient developed clinical symptoms highly suggestive of hyperthyroidism. Two and one half months after completion of therapy, the patient developed severe thyrotoxicosis, which, in retrospect, appears to have met the criteria for thyroid storm. This case history illustrates a previously unreported, life-threatening complication of external-beam radiation that should be considered in patients receiving IMRT therapy involving the thyroid. Diagnosis of the patient's hyperthyroidism and probable thyroid storm was difficult to recognize because of the significant overlap between the signs and symptoms of severe thyrotoxicosis and the expected toxicities of his cancer therapy.
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CASE STUDY |
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A 43-year-old nonsmoker with unremarkable past medical and family histories presented with an enlarging mass in his left neck. For one month he had noted fatigue and left otalgia, and had expectorated bright red blood when waking up. He had no weight loss, fevers, chills, dysphagia, or night sweats. Examination demonstrated a bilateral base of tongue mass extending onto the left tonsil; a biopsy revealed poorly differentiated squamous cell carcinoma. A positron emission tomography/computed tomography (CT) scan confirmed a left base of tongue and tonsil tumor, crossing midline toward the right measuring 2.4 x 4.2 x 3.6 cm, extending to the base of the epiglottis and pre-epiglottic space, and causing deviation of the airway toward the right. There was also abnormal fluorodeoxyglucose uptake in the left level II and III lymph nodes as well as the right level II lymph nodes; the largest node measured 2.2 x 2.2 cm. The thyroid gland was symmetric and normal in size. The patient's case was reviewed at our institution's comprehensive head and neck tumor board, where a consensus recommendation for treatment was developed. He received neoadjuvant chemotherapy with docetaxel, infusional 5-fluorouracil, and cisplatin [1, 2]. He tolerated chemotherapy poorly and did not receive a planned third cycle because of grade 3 stomatitis and dehydration requiring hospitalization. Subsequently, he went on to receive intensity-modulated radiation therapy (IMRT) (Fig. 1) with concurrent weekly carboplatin (area under the concentration–time curve of 1) and paclitaxel (30 mg/m2) [2, 3]. The patient underwent a 10-field IMRT with 6-MV x-rays, at a dose of 6,930 cGy in 33 fractions to the left base of tongue and involved upper bilateral cervical nodes, and 5,610 cGy in 33 fractions to clinically uninvolved cervical nodes. In this patient, the thyroid volumes that received 30 Gy and 50 Gy were 91% and 39%, respectively (Fig. 1). The treatment resulted in a complete tumor response.
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During treatment, after 1,470 cGy and one cycle of concurrent chemotherapy, the patient developed paranoid ideation, auditory hallucinations, aggressive episodes, and early morning confusion. The concurrent chemotherapy was therefore stopped. At this time he developed mucositis as well as dysphagia and weight loss. Morphine was discontinued and the patient was seen by psychiatry and placed on quetiapine. He appeared to improve somewhat and was started on a transdermal fentanyl patch and hydrocodone/acetaminophen elixir. By completion of the IMRT, he had developed grade 3 dermatitis, grade 2 mucositis, and grade 1 xerostomia. He lost 5 pounds overall (3% body weight) during the course of treatment and no treatment breaks were required.
Two and one half weeks after completion of IMRT, the patient presented for an unscheduled visit complaining of loss of appetite and energy, diurnal hypersomnia, lethargy, an additional 4-pound weight loss, and increased mouth and throat pain. On examination, he was afebrile at 98.8°F but tachycardic at 114 bpm. He had grade 3 mucositis and new onset of bilateral 1+ pedal edema. These symptoms were felt to be related to typical side effects from his treatment. He was followed closely for toxicity management. At 1 month post-treatment, he had lost 10 pounds as a result of continuing mucositis and dysphagia. At 2 months, he began experiencing nausea and vomiting, and continued to have periods of confusion. His temperature was 100.1°F and pulse was 124 bpm. He had then gained 11 pounds as a result of increased edema in his lower extremities and face. Chest x-ray and urinalysis were normal, and head CT and lumbar puncture were unremarkable. CT of the neck, chest, abdomen, and pelvis with and without iodine contrast showed no evidence of disease recurrence. The patient was started on furosemide and antiobiotic prophylaxis, and was closely monitored.
Approximately 3 months post-IMRT, the patient was admitted to the hospital after presenting with intractable nausea and vomiting and a 20-pound weight loss. He remained afebrile at 98.7°F, but his pulse was 150 bpm. An electrocardiogram showed sinus tachycardia. He did not have leukocytosis or abnormal liver function, but his free T4 was slightly elevated to 2.33 (normal, 0.78–2.19 ng/dl) and his thyroid-stimulating hormone (TSH) was suppressed (Fig. 2A, 2B). His basic metabolic panel, cortisol, adrenocorticotropic hormone, amylase, and lipase levels, and abdominal CT and magnetic resonance imaging of the brain were all normal. He was treated for dehydration and ketosis, and evaluation for infection was negative. At that time, the etiology of these symptoms was thought to be multifactorial, related mainly to poor nutrition and dehydration from his nausea and vomiting. His mental status changes were attributed to heavy narcotic use. The patient was discharged and followed closely as an outpatient.
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Three and one half months following IMRT, a repeat free T4 was 6.99, but the clinical significance of this result and the possibility that the patient was experiencing thyroid storm was not recognized. By the time of his next outpatient visit at 4.5 months, his free T4 had decreased to normal, at 1.4, and his clinical status had improved (Fig. 2A, 2B). His thyroid function was closely monitored subsequently (Fig. 2). At 5.5 months post-IMRT, he had developed biochemically and clinically evident hypothyroidism (Fig. 2), was started on levothyroxine, and was continued on furosemide. At 9 months post-IMRT, the patient's TSH level remained elevated and his levothyroxine was increased from 0.1 µg to 0.15 µg, resulting in iatragenic subclinical hyperthyroidism with a normal free T4 level and a suppressed TSH level on follow-up at 10 months. His levothyroxine was adjusted appropriately and he has experienced no recurrence of his thyrotoxicosis.
Currently, the patient is 16 months since the end of his treatment without clinical or radiographic evidence of cancer recurrence. Thyroid function studies remain within the normal range on replacement, and no anatomic thyroid abnormalities have been detected in four consecutive CT scans. The patient continues to improve monthly.
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DISCUSSION |
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Thyroid storm, or life-threatening thyrotoxicosis, is a rare medical emergency with a 20%–30% mortality rate in the treated patient [4–6]. The clinician is faced with a clinical diagnostic challenge because it is the severity of the clinical manifestations of the thyrotoxicosis rather than simply the levels of thyroid hormone that distinguish thyroid storm from uncomplicated thyrotoxicosis [5–7]. A similar situation is seen in the distinction between severe hypertension and malignant hypertension, where the distinction is based on the absence or presence of organ dysfunction (papilledema). In the case of thyroid storm, Burch and Wartofsky [7] delineated diagnostic criteria with a point system for level of dysfunction in various systems including thermoregulatory, central nervous, gastrointestinal-hepatic, and cardiovascular (Table 1). Determining this patient's diagnosis was confounded by the overlap between head and neck cancer treatment-related side effects (low-grade fever, agitation, lethargy, nausea, and mild tachycardia) and the criteria used to distinguish thyrotoxicosis from thyroid storm (fever, agitation, lethargy, and tachycardia). The use of hydrocodone/APAP may have masked thermoregulatory dysfunction in addition to being a plausible explanation for his mental status changes.
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The clinical diagnosis of thyroid storm versus severe thyrotoxicosis is difficult, but the clinical findings remain the same regardless of which term is used. In the Burch and Wartofsky scoring system, a score
45 is highly suggestive of thyroid storm. Approximately 2 weeks following completion of IMRT, our patient developed psychosis, lethargy, pedal edema, and mild tachycardia. Thyrotoxicosis with these symptoms would fulfill the criteria for the diagnosis of thyroid storm with a score of 45. When the patient presented with intractable vomiting at 3 months, the Burch and Wartofsky score would have been 80 based on the patient's symptoms at that time (Table 1). Although it is clinically difficult, or perhaps impossible, to determine which of these symptoms were a result of thyrotoxicosis and which were side effects from his cancer therapy, it is likely that many of his symptoms were in fact from the thyrotoxicosis and that early recognition of his thyrotoxicosis would have resulted in the administration of therapy directed at the thyrotoxicosis and hastened the patient's symptomatic recovery. If the symptoms were solely from the thyrotoxicosis rather than side effects from the cancer therapy, the patient was in thyroid storm based on the Burch and Wartofsky criteria and the failure to recognize the diagnosis could have resulted in a mortal outcome. When the patient was an inpatient at 3 months post-IMRT, his thyroid dysfunction remained undiagnosed, so neither an endocrinology consultation nor specific therapies for thyrotoxicosis were undertaken. By the time of his 4.5-month follow-up visit, the thyrotoxicosis had spontaneously resolved (Fig. 2).
Adequate management of thyrotoxicosis, or its more serious subcategory of thyroid storm, depends on successful diagnosis and the use of medications to block the production and effects of thyroid hormone. Recommendations include inhibition of new thyroid hormone production with propylthiouracil or methimazole, inhibition of thyroid hormone release with stable iodide like Lugol's solution, β-adrenergic blockade, and acetaminophen as an antipyretic. Glucocorticoids, i.v. fluids and other supportive measures are used as clinically indicated [5, 6].
The precise pathophysiologic mechanism that causes thyroid storm is not fully understood. Hypotheses include an increase in the amount of free thyroid hormones [5], by activation of the adrenergic system [7] or by an interaction between excessive circulating thyroid hormone and the adrenergic system [7]. The mean free T4 concentration has been shown to be higher in patients with thyroid storm than in those with more typical thyrotoxicosis, but there is substantial overlap in the levels [8]. Known precipitant factors of thyroid storm include infection, surgery, radioiodine therapy, iodinated contrast dyes, withdrawal of antithyroid drug therapy, Graves' disease, hypersecretory thyroid carcinoma, diabetic ketoacidosis, trauma, cerebrovascular accident, myocardial infarction, parturition, and pulmonary thromboembolism [4, 5, 7, 9]. In a review of the literature, McDermott et al. [4] noted that radioiodine-induced thyroid storm is a rare event, occurring in 0.34% (10 of 2,975) of patients, with the interval from radioiodine dose to diagnosis of thyroid storm in the range of 0.5–20 days and an outcome of 25% mortality. The radioiodine dose given and the size of the thyroid gland appear to not be related to radioiodine-induced thyroid storm [9].
The most plausible explanation for this patient's clinical course is thyroidal injury from the IMRT causing excessive release of stored thyroid hormones followed by hypothyroidism from the inability of the damaged thyroid to continue thyroid hormone production after the stores were depleted. A similar pattern is classically observed in patients with subacute thyroiditis and chronic lymphocytic thyroiditis, although these do not invariably result in permanent hypothyroidism. The etiology of IMRT damage to the thyroid could be either a direct cytotoxic effect of the radiation on the thyroid or an indirect effect from the induction of thyroid autoimmunity, as observed after the Chernobyl accident [10, 11]. The time course favors the former. Lacking comprehensive pre-IMRT evaluation of the patient's thyroid, the possibility of exacerbation of a pre-existing thyroid disorder cannot be conclusively ruled out, but the lack of pre-existing symptoms or structural thyroid abnormalities makes this postulate less likely. The possibility of iodine-induced thyrotoxicosis, as might have occurred with the administration of contrast agents, generally occurs in patients with multinodular goiters (not present in this case) and is not known to result in hypothyroidism. The patient is also likely to be at increased risk of developing thyroid cancer in the coming years related to the radiation exposure to the thyroid, so evaluation of the thyroid by ultrasound should be performed periodically along with regular palpation of the thyroid for nodules.
To our knowledge, this is the first reported case in the literature of thyroid storm temporally related to the administration of external-beam radiation therapy. In the U.S., head and neck cancers account for 3.2% of all cancers and 2.2% of all cancer deaths [12]. In the 1960s through 1980s, the only curative treatment consisted of surgery and radiotherapy. A paradigm shift occurred in the 1990s with studies showing that chemoradiation can achieve comparable tumor control with organ preservation, becoming an acceptable treatment option for locally advanced and unresectable head and neck carcinomas [12].
External-beam radiotherapy has been known to induce various thyroid disorders, such as primary hypothyroidism (3%–92%), Graves' disease (0.1%–2%), silent thyroiditis (0.6%–3%), Hashimoto's thyroiditis (0.7%–48%), Graves' ophthalmopathy (0.2%–1.3%), benign adenoma (0.6%–3%), and thyroid cancer (0.35%) [13–16]. External-beam radiation is known to promote the release of excessive thyroid hormones during treatment, thereby suppressing TSH via negative feedback (Fig. 2A) [16]. The etiology of radiation-induced acute injury to the thyroid includes autoimmune reactions, parenchymal cell damage, and vascular damage [13]. Thyroid damage is initially manifested within 6 months [17]. The peak incidence of primary hypothyroidism occurs 2–3 years after treatment, with approximately 50% of these events occurring within the first 5 years of radiotherapy [13, 15, 18]. A higher dose portends a shorter latency period [18], and there appears to be no time when the incidence levels off. Studies confirm that radiation dose-volume factors of the thyroid correlate with the incidence of hypothyroidism: the volume of the thyroid receiving 10 Gy (V10), V20, and V30 have a significant impact on the peak level of serum TSH [19] and the development of hypothyroidism [20]. Interestingly, the experience at our institution with head and neck cancer patients treated with concurrent carboplatin, paclitaxel, and IMRT has been an incidence of hypothyroidism of 47% (56 of 119) at 1.1 years [21], suggesting a shorter latency with IMRT. We believe this is related to the higher dose to a larger portion of the gland from IMRT tangential beam arrangement; older conventional two- and three-dimensional radiation fields shielded the midline of the neck, including the thyroid. In this patient, the thyroid volumes (shown in yellow, Fig. 1A) that received 30 Gy and 50 Gy were 91% and 39%, respectively. The contribution of chemotherapy to this patient's thyroid storm is unknown; no reports of thyroid storm induced by the chemotherapeutic agents used in this patient have been published. Radiosensitization of normal tissues, however, is a well-known phenomenon of many chemotherapeutics.
A number of institutions are using IMRT because of its ability to deliver a highly conformal dose to the tumor(s) while sparing normal surrounding tissue from high radiation doses [22–24]. This capability, in addition to the lack of organ motion, make IMRT an ideal treatment modality for head and neck cancers [23]. However, there is insufficient understanding of the technology's potential side effects [24]. Drawbacks to IMRT are illustrated in this patient. First, IMRT deposits low doses of radiation to a significantly larger volume of normal tissue [22]. This may require longer follow-up because of the risk for secondary malignancies or cardiovascular events [22]. Second, the sharp dose gradients created in IMRT present a greater risk for marginal tumor miss [22, 23]. Finally, IMRT can create "hot spots," or doses that are higher than the prescription dose. This dose inhomogeneity can potentiate post-treatment complications [23]. It is recommended that thyroid tissue be regarded as an organ-at-risk for radiation damage during IMRT treatment planning, and appropriate steps be taken to ensure that the thyroid dose is kept to minimum levels in future head and neck cancer treatment.
It is difficult to find a definitive link between IMRT and thyroid storm because of overlapping signs and symptoms from standard treatment, the lack of a standardized test for the diagnosis of radiation-induced thyroid damage, as well as the absence of previous reports on this complication in the literature. This case illustrates how oncologists, appropriately focused on cancer and common treatment complications, can overlook other medical conditions. Even though thyrotoxicosis can rarely occur in the setting of chemoradiotherapy for locally advanced head and neck cancer (LAHNC), patients receiving chemoradiotherapy for LAHNC commonly develop significant symptoms as a consequence of standard treatment. These patients are also at significant risk for other complications related to their tumor, treatment, and comorbid illnesses. Accurately diagnosing and treating these complications provides a challenge to the medical and radiation oncologist. Physicians need to be aware of the clinical manifestations of abnormal thyroid function during treatment in these patients because the symptoms related to thyrotoxicosis can have significant overlap with the commonly observed treatment toxicities and the medication regimens used in this patient population.
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AUTHOR CONTRIBUTIONS |
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Conception/Design: Roberto Diaz, Anthony J. Cmelak
Administrative support: Roberto Diaz
Provision of study materials: Patrick B. Murphy, Anthony J. Cmelak
Collection/assembly of data: Roberto Diaz, Marc D. Blakey, Patrick B. Murphy, Anthony J. Cmelak
Data analysis: Roberto Diaz, Marc D. Blakey, A. Keith Cryar, Anthony J. Cmelak
Manuscript writing: Roberto Diaz, Marc D. Blakey, A. Keith Cryar, Anthony J. Cmelak
Final approval of manuscript: Roberto Diaz, Marc D. Blakey, Patrick B. Murphy, A. Keith Cryar, Anthony J. Cmelak
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ACKNOWLEDGMENT |
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Marc D. Blakey is now affiliated with Mercy Health Partners, Knoxville, TN. We thank Ms. Michelle Johnson for her efforts in data acquisition and outstanding technical assistance.
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